Thursday, April 25, 2013

Mapping the Epigenetic Landscape

Screen shot from the Transcriptional Regulation and Epigenetic Landscape Explorer's Topographic Landscape tool showing a landscape inferred from publicly available gene expresion data for human cell types. 
As reader's of this blog may or may not know, I lead a dual life as an outdoor person/hillmap maintainer and a software engineer/data scientists focused on biological research. Links between the code behind hillmap and the code I write in my day job  are rare and usually too technical to be interesting to non coders but recently I had the chance to help with a tool that used topographic maps of abstract landscapes to visualize the results of some cutting edge biological research.

Lead by Merja Heinaniemi scientists from the Institute for Systems Biology where I work and groups from Finland and Luxembourg collaborated to infer an "epigenetic landscape" from a curated set of publicly available gene expresion data for human cell types (Heinaniemi, Merja. et all "Gene-pair expression signatures reveal lineage control"Nature Methodspress release).

Waddington's now classic depiction of the epigenetic landscape of dividing valleys/cell types which an embryonic cell may procede into first appeared in his 1957 book The Strategy of the Genes.
Conrad Hal Waddington proposed the concept of the epigenetic landscape in the 1950's as a metaphor for the way in wich a stem cell, like a marble rolling down a slope, can develop into any number of cell types (valleys) in the metaphor but cannot hop between cell types or return up the hill to its original state with out some significant perturbation.

Waddington illustrated his metaphor with beautiful pen and ink drawings like the one above. I won't attempt to describe the details of the analysis done to infer the landscape as I did not contribute to it, but I did help produce a grey scale topographic map of the results inspired by Waddington's drawings which you can see in the top picture and the one below or in an interactive map viewer under the "Tools->Topographic Landscape" menu item at the paper's companion webapp the Transcriptional Regulation and Epigenetic Landscape Explorer.

As fetal cells develop they progress down the valley to the left of this screen shot of the inferred landscape.
The care that went into Waddington's illustrations has always reminded me of classic USGS topographic maps. The metaphor of a landscape is not perfect; Waddington's valleys split as the marble procedes downhill while real world valleys tend to come together as alpine streams which then join to form major rivers. However, a landscape akin to Waddington's does apear near the peaks of high mountains where streams and vallies shoot off in all directions away from the summit before recombining at lower elevations.

The furcating valleys down which a skier perched on the crater rim of Mount Saint Helens may proceed down. (View in hillmap)
The south slopes of Mount Saint Helens are particularly akin to Waddigton's concept. Rocky ridges and ash deposites from the 1980 eruption have beem sculpted by erosive forces into serpentine ridges and valleys. I skied the most popular winter route last year, "The Worm Flows" which is named after these features and bears a striking resemblance to Waddington's drawings.

Perched on a the summit, a skier or climber has the potential to choose a line reaching any number of places. As with Waddington's marble dropping down into the wrong valley, as we have all done at one time or another, will leave him in a position where a great deal of energy is required to return to the desired location (usually the car).

A rugged portion of the inferred landscape I attempted to color with the USGS pallet. I imagine these basins as holding high alpine lakes though they represent abstract sets of similar cell types.
The high tarns above Chaffin Lake in the Bitterroots occupy a similar landscape. (View in Hillmap)
This was also my first attempt at actually making map layers. A long term goal of hillmap is to include some custom topographic map layers and this was a step down that road (or valley) in terms of learning the software required.

The view from the summit of Mount Saint Helens as my ski partners find their line through the landscape.

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